Asymmetric Synthesis of P-Amino Acids

Therefore we were interested in the development of a method for the asymmetric synthesis of cyclic and acyclic 5-hydroxy-P-amino acids 83-85 (Fig. 1.3.8). 

3 Asymmetric Synthesis Based on Sulfonimidoyl-Substituted Allyltitanium Complexes 

3 3O Asymmetric synthesis of protected cyclic 5-hydroxy-P-amino acids. 

This study was supported by the Deutsche Forschungsgemeinschaft (SFB 380, Asymmetric Synthesis with Chemical and Biological Methods, and GK 440 Methods in Asymmetric Synthesis ) and the Griinenthal GmbH, Aachen. The work described here would not have been possible without the dedicated efforts of my coworkers who are named in the references and to whom I am grateful for their contributions. 

Muller, J. Decker, R. Hainz, Tetrahedron Lett. 1995, 36, 7433-7435. 

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Cardillo, G. Tomasini, C. Asymmetric Synthesis of P-Amino Acids and a-Substituted P-Amino Acids, Chem. Soc. Rev. 1996, 25, 117-128. 

Yamamoto, Y Asao, N. Tsukada, N. Asymmetric Synthesis of P-Amino Acids and P-Lactam Derivatives via Conjugate Addition of Metal Amides, AiJv. Asym. Syruh., Vol. 3, Hassner, A., Ed. JAI Press, Stamford, CT, 1998. 

Asymmetric synthesis of P-amino acid esters. The chiral diazaborolidine 1 (16,155) also effects diastereo- and enantioselective reactions of (S)-r-butyl thiopro-ponoate (2) with N-benzyl or N-allyl aldimines 3 to form j3-amino acid esters 4, precursors to chiral irons-pAactams (5) in 90-99% ee. 

Vesely, J., Ihrahem, L, Rios, R., Zhao, G.-L., Xu, Y., Cdrdova A. (2007). Enantioselective organocatalytic conjugate addition of amines to a,p-unsaturated aldehydes one-pot asymmetric synthesis of p-amino acids and 1,3-diamines. Tetrahedron Letters, 48, 2193-2198. 

Myers JK, Jacobsen EN (1999) Asymmetric synthesis of P-amino acid derivatives via catalytic conjugate addition of hydrazoic acid to unsaturated imides. J Am Chem Soc 121 8959-8960... 

Gu, R.-L., Lee, I.S. and Sih, C.J., Chemo-enzymatic asymmetric synthesis of amino acids. Enantioselective hydrolyses of 2-phenyl-oxazolin-5-ones. Tetrahedron Lett., 1992, 33, 1953-1956 Crich, J., Brieva, R., Marquart, P., Gu, R.-L., Flemming, S. and Sih, C.J., Enzymic asymmetric synthesis of a-amino acids. Enantioselective cleavage of 4-substituted oxazolin-5-ones and thiazolin-5-ones. J. Org. Chem., 1993, 58, 3252-3258. 

During our investigations on asymmetric C—C bond formation reactions via conjugate addition of SAMP hydrazones to various a,(3-unsaturated Michael acceptors, it occurred to us to use the chiral hydrazine auxiliary S AM P as a nitrogen nucleophile and a chiral equivalent of ammonia in aza-Michael additions. Thus, we developed diastereo- and enantioselective 1,4-additions for the synthesis of P-amino acids and P-aminosulfonates [14, 15]. 

Prior to the beginning of our work on sitagliptin, there had been some reports in the literature of catalytic asymmetric hydrogenation of enamines to access chiral secondary amines [19]. The synthesis of P-amino acids had also been established by catalytic asymmetric hydrogenation of enamides [20]. All these reports relied on N-acylenamines as substrates, since it was believed that the N-acyl group was required in order to achieve good reactivity and selectivity [21]. 

Asymmetric Mannich reactions provide useful routes for the synthesis of optically active p-amino ketones or esters, which are versatile chiral building blocks for the preparation of many nitrogen-containing biologically important compounds [1-6]. While several diastereoselective Mannich reactions with chiral auxiliaries have been reported, very little is known about enantioselective versions. In 1991, Corey et al. reported the first example of the enantioselective synthesis of p-amino acid esters using chiral boron enolates [7]. Yamamoto et al. disclosed enantioselective reactions of imines with ketene silyl acetals using a Bronsted acid-assisted chiral Lewis acid [8]. In all cases, however, stoichiometric amounts of chiral sources were needed. Asymmetric Mannich reactions using small amounts of chiral sources were not reported before 1997. This chapter presents an overview of catalytic asymmetric Mannich reactions. 

Serine hydroxymethyltransferase is a PLP-dependent aldolase. It catalyzes interconversion between glycine and various P-hydroxy-a-amino acids, such as serine and threonine, via formation of a quinoid intermediate derived from PLP with the amino acid substrate (Scheme 2.9). This aldolase-type reaction is of interest as an asymmetric synthesis of a-amino acids via C-C bond formation. 

Juaristi, E., Garcia-Barradas, O. Asymmetric addition of amines to a, 3-unsaturated esters and nitriles in the enantioselective synthesis of P-amino acids. Enantioselective Synthesis of. beta.-Amino Acids 1997, 139-149. 

Parallel to the above approach efficient synthesis of P-amino acid derivatives by the use of Sn(II) enolates and a-aminoesters have been carried out by Japanese workers [90]. The most recent asymmetric synthesis of a (-h)-6-epi PS-5 carbapenem building block through this methodology (Scheme 33), involved... 

P-Amino acids have been shown to be an important class of compounds both in biomedical research and the pharmaceutical industry. These structural motifs are present in p-lactams and P-peptides and also serve as chiral templates for the synthesis of other pharmaceuticals. Perhaps the most convenient and straightforward method for the synthesis of P-amino acids is the catalytic asymmetric hydrogenation of p-(acylamino)acrylates 151. Some success has been reported for the Rh-catalyzed asymmetric hydrogenation of ( ) and (Z)- isomers of p-(acylamino)acrylates using chiral phosphorous ligands such as Me-DuPhos, DuanPhos, TangPhos, and other ligands. ... 

Other electrophiles, such as Michael acceptors, can also be involved in the a-alkylation step. This has been exploited in the conjugate addition of enantiopure lithium amides 60 to unsaturated esters 61, followed by trapping of the resulting enolate with alkylidene malonates. This constitutes a useful methodology for the asymmetric synthesis of p-amino-a-substituted carboxylic acid derivatives 62 (Scheme 11.24) [65]. 

Ager, D.J., Laneman, S.A. The synthesis of unnatural amino acids. In Blaser, H.-U., Schmidt, E. (Eds.), Asymmetric Catalysis on Industrial Scale. Wiley-VCH, Weinheim, 2004, p. 259. 

B. Lygo, P. G. Wainwright, A New Class of Asymmetric Phase-Transfer Catalysts Derived from Cinchona Alkaloids - Application in the Enantioselective Synthesis of a-Amino Acids , Tetrahedron Lett., 1997, 38, 8595-8598. 

Uraguchi D, Sorimachi K, Terada M (2004) Organocatalytic asymmetric aza-Friedel-Crafts alkylation of furan. J Am Chem Soc 126 11804-11805 Uraguchi D, Terada M (2004) Chiral Brpnsted acid-catalyzed direct Mannich reactions via electrophilic activation. J Am Chem Soc 126 5356-5357 Vachal P, Jacobsen EN (2000) Enantioselective catalytic addition of HCN to ketoimines. Catalytic synthesis of quaternary amino acids. Org Lett 2 867-870... 

Especially interesting is the possibility for asymmetric synthesis by employing amino acid derived ylide systems e.g. 33 Scheme 54), which allows the synthesis of optically active p, y-unsaturated aldehydes. ... 

Davis, F. A., Reddy, R. E., Portonovo, P. S. Asymmetric Strecker synthesis using enantiopure sulfinimines a convenient synthesis of a-amino acids. Tetrahedron Lett. 1994, 35, 9351-9354. 

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